1. Field of Invention
The present invention relates to improved methods of preparing 3-phenoxyazetidines and their 1-carboxamide derivatives. The 3-phenoxyazetidines and 3-phenoxy-1-azetidinecarboxamides have pharmacological activity and use in the pharmaceutical field.
2. Information Disclosure Statement
The preparation of 3-phenoxyazetidines by hydrogenolysis of the corresponding 3-phenoxy-1-(.alpha.-methylbenzyl)azetidine or 1-diphenylmethyl-3-phenoxyazetidine is disclosed in U.S. Pat. No. 4,379,151. In that disclosure, 1-diphenylmethyl-3-phenoxyazetidine is derived by reacting phenol and sodium amide followed by reaction of the resulting phenolate with 1-diphenylmethyl-3-methanesulfonyloxyazetidine and the compounds have anorexigenic activity.
Anderson, A. G. and Lok, R. in J. Org. Chem. 37, 3953 (1972) disclosed preparation of 1-benzhydryl-3-methoxy (or ethoxy) azetidine via reaction of 1-diphenylmethyl-3-methanesulfonyloxyazetidine with methyl or ethyl alcohol.
The preparation of certain N-loweralkyl-3-phenoxy-1-azetidinecarboxamides which are useful as anticonvulsants from reaction of 3-phenoxyazetidines and isocyanates is disclosed in U.S. Pat. No. 4,226,861.
The preparation of 3-phenoxy-1-azetidine carboxamides is disclosed in copending application U.S. Ser. No. 409,476 filed Aug. 19, 1982. The compounds have anticonvulsant properties as demonstrated by the same methods as in U.S. Pat. No. 4,226,861
The preparation of N-formyl and N-hydroxymethyl-3-phenoxy-1-azetidinecarboxamides having anticonvulsant activity utilizing certain of the 3-phenoxy-1-azetidine carboxamides in reaction with formic acid or formaldehyde is disclosed in copending application U.S. Ser. No. 414,101 filed Sept. 2, 1982. The compounds have anticonvulsant properties as demonstrated by the same methods as in U.S. Pat. No. 4,226,861.
Features of the method of the present invention absent in the prior art are at least as follows:
(a) The 1-diphenylmethyl-3-phenoxyazetidine precursors are novelly prepared in the present invention from a phenol, alkali metal base and 1-diphenylmethyl-3-alkane (or benzene) sulfonyloxyazetidine using a phase transfer catalyst such as tetrabutylammonium bromide, and
(b) Hydrogenolysis of the 1-diphenylmethyl-3-phenoxyazetidine to remove the protecting group and to produce the 3-phenoxyazetidine in a mixture with diphenylmethane by-product is conducted in the presence of an azetidine-stabilizing amount of a tertiary organic base such as triethylamine to prevent formation of a dimerization product found in the practice of prior art methods, which dimer has the following general structure: ##STR1##
Both features a and b promote high yields and in addition, when the azetidine-stabilizing tertiary organic base is used, a mixture of 3-phenoxyazetidine and by-product diphenylmethane can be used without purification to prepare the carboxamides which can be isolated in relatively pure form by washing out the diphenylmethane. Prior art mixtures wherein no stabilizing amine is used contain about 15 parts by weight of the foregoing Dimer A to 85 parts by weight of the desired 3-phenoxyazetidine. As a result, when this mixture is not purified before reacting with methylisocyanate or nitrourea, in carboxamide preparation, a compound having the structure Dimer B results which is difficult to remove: ##STR2##